The Molecular Function of σ Receptors: Past, Present, and Future

The σ1 and σ2 receptors are drug targets for several conditions. However, despite considerable pharmacological interest, relatively little is known about their molecular functions. The prevailing model of σ1 receptor function is that it is a chaperone protein that acts as a pluripotent modulator of other signaling pathways. This may be true, but current evidence does not rule out other models. Recent structural and biochemical work shows that the σ1 receptor is a single-pass transmembrane protein that exists in multiple oligomeric states. Ligands differentially modulate these states, and recent crystal structures offer a potential explanation. Novel loss-of-function mutations in the σ1 receptor that cause neuromuscular disease continue to emerge. Mapping these mutations onto the σ1 receptor structure reveals structural rationales for their effects. The σ2 receptor has recently been cloned. It has been identified as TMEM97, a four-pass transmembrane protein possibly involved in cholesterol metabolism. The σ1 and σ2 receptors are enigmatic proteins that have attracted attention for decades due to the chemical diversity and therapeutic potential of their ligands. However, despite ongoing clinical trials with σ receptor ligands for multiple conditions, relatively little is known regarding the molecular function of these receptors. In this review, we revisit past research on σ receptors and discuss the interpretation of these data in light of recent developments. We provide a synthesis of emerging structural and genetic data on the σ1 receptor and discuss the recent cloning of the σ2 receptor. Finally, we discuss the major questions that remain in the study of σ receptors. The σ1 and σ2 receptors are enigmatic proteins that have attracted attention for decades due to the chemical diversity and therapeutic potential of their ligands. However, despite ongoing clinical trials with σ receptor ligands for multiple conditions, relatively little is known regarding the molecular function of these receptors. In this review, we revisit past research on σ receptors and discuss the interpretation of these data in light of recent developments. We provide a synthesis of emerging structural and genetic data on the σ1 receptor and discuss the recent cloning of the σ2 receptor. Finally, we discuss the major questions that remain in the study of σ receptors. a ligand that activates a receptor to elicit a biological signaling response. a ligand that inactivates a receptor to prevent or attenuate a biological signaling response. a form of scanning probe microscopy that uses a physical probe to scan a surface, providing an image with subnanometer resolution. an enzyme involved in the synthesis of cholesterol/ergosterol. It moves a double bond between carbons C9 and C8 to C8 and C7. a class of protein that assists in the folding of other proteins. Many are essential parts of the cell’s protein synthesis machinery. a technique in which an antibody against a ‘bait’ protein attached to beads is used to remove the bait, and any proteins associated with it, from solution. a gene editing system that uses the enzyme Cas9 with an associated guide RNA molecule to make modifications to specific regions of an organism’s DNA. a member of a diverse family of seven-pass transmembrane receptor that couples to G proteins to transmit a biological signal. a small molecule second messenger that activates the IP3 receptor, triggering calcium release from the ER. a transmembrane protein that, when activated, allows specific ions to flow along their concentration gradient from one side of a membrane to another. a specialized region of the ER membrane that forms a contact with the mitochondrial membrane, thought to be important for the control of calcium homeostasis, lipid metabolism, and autophagy. the part of a chemical structure that is responsible for its specific interactions. a technique used to show that two proteins are within close proximity to one another. Cells are stained with primary antibodies against the proteins of interest. Secondary antibodies with complementary oligos are then added to bind to the primary antibodies. If the secondary antibodies are in close proximity, the oligos will anneal. Enzymes are added to initiate rolling DNA synthesis. a class of techniques used to show that two light-sensitive molecules are in close proximity to one another. A light-sensitive molecule is excited at a wavelength specific to that molecule. The excited molecule emits a photon at a wavelength that will excite the other light-sensitive molecule if the two are within close spatial proximity. an RNA interference method that uses a short interfering RNA (siRNA) of 20–25 bp to reduce expression of the target gene through the RNA-induced silencing complex (RISC) pathway. a cellular stress response to misfolded proteins in the ER lumen. The UPR includes a complex signaling cascade to fold or remove the unfolded proteins, or to induce apoptosis.